Special Issue "Novel Approaches for Targeting Metalloproteinases"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (15 October 2021).

Special Issue Editor

Dr. Salvatore Santamaria
E-Mail Website
Guest Editor
Department of Immunology and Inflammation, Imperial College London, Centre for Haematology, 5th Floor Commonwealth Building, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
Interests: ADAMTS; proteoglycans; monoclonal antibodies; exosite inhibitors; enzyme kinetics; proteomics; proteoglycanomics; phage display

Special Issue Information

Dear Colleagues,

Metalloproteinases play key roles in physiological processes such as embryonic development, wound healing, angiogenesis, and blood coagulation, as well as pathologies like arthritis, cardiovascular disease, and cancer. In the therapeutic context, either decreasing or increasing the activity of a particular metalloproteinase may be ideal.  This can be achieved, for example, through the action of molecules able to bind to substrate-binding sites (exosites) present on the ancillary domains of these enzymes or interfere with their transcriptional or post-translational regulation.

Potential contributors are invited to submit papers concerning modulators of metalloproteinase activity in any pharmaceutical or related context. Particularly welcome are studies involving exosite inhibitors/enhancers, substrate mimetics, natural products, and glycoconjugates, as well as peptides, aptamers, monoclonal antibodies, and engineered proteins. Novel approaches for the therapeutic delivery of these reagents are also appreciated.

I look forward to reading your submission.

Dr. Salvatore Santamaria
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metalloproteinases
  • exosites
  • inhibitors
  • enhancers

Published Papers (8 papers)

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Research

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Article
Coumarin Derivatives Act as Novel Inhibitors of Human Dipeptidyl Peptidase III: Combined In Vitro and In Silico Study
Pharmaceuticals 2021, 14(6), 540; https://doi.org/10.3390/ph14060540 - 05 Jun 2021
Viewed by 925
Abstract
Dipeptidyl peptidase III (DPP III), a zinc-dependent exopeptidase, is a member of the metalloproteinase family M49 with distribution detected in almost all forms of life. Although the physiological role of human DPP III (hDPP III) is not yet fully elucidated, its involvement in [...] Read more.
Dipeptidyl peptidase III (DPP III), a zinc-dependent exopeptidase, is a member of the metalloproteinase family M49 with distribution detected in almost all forms of life. Although the physiological role of human DPP III (hDPP III) is not yet fully elucidated, its involvement in pathophysiological processes such as mammalian pain modulation, blood pressure regulation, and cancer processes, underscores the need to find new hDPP III inhibitors. In this research, five series of structurally different coumarin derivatives were studied to provide a relationship between their inhibitory profile toward hDPP III combining an in vitro assay with an in silico molecular modeling study. The experimental results showed that 26 of the 40 tested compounds exhibited hDPP III inhibitory activity at a concentration of 10 µM. Compound 12 (3-benzoyl-7-hydroxy-2H-chromen-2-one) proved to be the most potent inhibitor with IC50 value of 1.10 μM. QSAR modeling indicates that the presence of larger substituents with double and triple bonds and aromatic hydroxyl groups on coumarin derivatives increases their inhibitory activity. Docking predicts that 12 binds to the region of inter-domain cleft of hDPP III while binding mode analysis obtained by MD simulations revealed the importance of 7-OH group on the coumarin core as well as enzyme residues Ile315, Ser317, Glu329, Phe381, Pro387, and Ile390 for the mechanism of the binding pattern and compound 12 stabilization. The present investigation, for the first time, provides an insight into the inhibitory effect of coumarin derivatives on this human metalloproteinase. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Article
Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)
Pharmaceuticals 2021, 14(3), 203; https://doi.org/10.3390/ph14030203 - 28 Feb 2021
Cited by 2 | Viewed by 915
Abstract
Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous [...] Read more.
Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Article
Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
Pharmaceuticals 2021, 14(3), 197; https://doi.org/10.3390/ph14030197 - 27 Feb 2021
Cited by 2 | Viewed by 792
Abstract
Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other [...] Read more.
Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). Here, in part II, we report further efforts to optimize potency and selectivity. We hope that a hydroxamic acid meprin α inhibitor probe will help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Communication
(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone
Pharmaceuticals 2021, 14(2), 85; https://doi.org/10.3390/ph14020085 - 24 Jan 2021
Viewed by 623
Abstract
Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, [...] Read more.
Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Review

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Review
Targeting Cartilage Degradation in Osteoarthritis
Pharmaceuticals 2021, 14(2), 126; https://doi.org/10.3390/ph14020126 - 05 Feb 2021
Cited by 2 | Viewed by 941
Abstract
Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated [...] Read more.
Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated cartilage degradation and to counteract cartilage damage by promoting growth factor-driven repair. Metalloproteinase-blocking antibodies are discussed, along with recent clinical trials on FGF18 and Wnt pathway inhibitors. We also considered dendrimer-based approaches being developed to deliver and retain such therapeutics in the joint environment. These may reduce systemic side effects while improving local half-life and concentration. Development of such targeted anabolic therapies would be of great benefit in the osteoarthritis field. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Review
Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer’s Disease
Pharmaceuticals 2021, 14(2), 86; https://doi.org/10.3390/ph14020086 - 24 Jan 2021
Cited by 5 | Viewed by 1054
Abstract
Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated [...] Read more.
Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer’s disease. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Review
The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors
Pharmaceuticals 2021, 14(1), 31; https://doi.org/10.3390/ph14010031 - 31 Dec 2020
Cited by 4 | Viewed by 1019
Abstract
Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on [...] Read more.
Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches, such as proteomics and N-terminomics, to identify new MMP substrates. We present some examples of new MMP substrates and their implications in regulating biological functions. By characterizing the roles and substrates of individual MMP, MMP inhibitors could be utilized more effectively in the optimal disease context or in diseases never tested before where MMP activity is elevated and contributing to disease progression. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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Review
Developments in Carbohydrate-Based Metzincin Inhibitors
Pharmaceuticals 2020, 13(11), 376; https://doi.org/10.3390/ph13110376 - 10 Nov 2020
Viewed by 717
Abstract
Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small [...] Read more.
Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models. Full article
(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)
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